CD8+ T Cell effector mechanisms against L. monocytogenes

University Of Iowa, Iowa City IA

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Abstract

DESCRIPTION (provided by applicant): CD8+ T cells, which respond to Listeria monocytogenes (LM)-derived peptides presented by both MHC class 1a and MHC class 1b molecules, are important mediators of adaptive immunity to LM in wild-type mice. In the Last grant period, we examined perfoin, IFN-gamma and TNF as effector mechanisms of CD8+ T cells in resistance to LM. Our studies demonstrate that these effector molecules are not required for CD8+ T cell resistance to LM infection. However, we also learned that perforin and IFN-gamma play key roles in regulating the normal expansion (perforin) and contraction (IFN-gamma) phases of MHC class 1a restricted CD8+ T cell homeostasis in H-2d MHC mice Importantly, the absence of one or both molecules resulted in elevated levels of memory CD8+ T cells after vaccination. Thus, the role of perforin and IFN-gamma as effector molecules in CD8+ T cell immunity to LM remains to be determined.We also demonstrated that vaccination of H2b MHC perforin- TNF- and perforin/TNF-deficient mice evoked high level antilisterial immunity that was based, at least in part, on CD8+ T cells. In H-2b MHC mice, both MHC class 1a (classical) and MHC class 1b (non-classical) restricted CD8+ T cells participate in antilisterial immunity. Like IFN-gamma, TNF is a pleiotropic cytokine with the capacity to participate in the normal regulation of CD8+ T cell homeostasis. Consistent with this notion and our previous results in H-2d MHC mice, we have preliminary evidence for altered homeostasis of LM antigen-specific CD8+ T cells in H-2b MHC perforin and/or TNF-deficient mice. It remains to be determined how perforin and/or TNF regulate CD8+ T cell homeostasis and whether common mechanisms are used in regulation of MHC class 1a and MHC class 1b restricted CD8+ T cells.Our long-term goal is to understand how memory CD8+ T cells are generated and provide immunity to intracellular pathogens. We will continue our analysis of the relationship between CD8+ T cell effector molecules, protective immunity and regulation of antigen-specific CD8+ T cell homeostasis through the following specific aims.Specific Aim-1. Determine the protective capacity, repertoire utilization and functional avidity of LM-epitope specific memory CD8+ T cells from H 2d MHC perforin-, IFN-gamma-, perforin/IFN-gamma-deficient and WT mice. Specific Aim-2. Define the impact of perforin and/or TNF-deficiency on the homeostasis of MHC class Ia and class 1b restricted CD8+ T cells. Specific Aim-3. Differentiate between intrinsic and extrinsic regulatory roles for perforin and TNF in CD8+ T cell homeostasis.